Substituted imidazoles useful in the treatment of inflammatory disease
First Claim
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1. A compound of Formula I ##STR37## wherein:
- R1 is phenyl, substituted phenyl where the substituents are selected from the group consisting of C1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile, or pyridinyl;
R2 is phenyl, substituted phenyl where the substituents are selected from the group consisting of C1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile or pyridinyl where the pyridinyl is optionally C1-4 alkyl substituted;
R3 is hydrogen, SEM, C1-5 alkoxycarbonyl, aryloxycarbonyl, arylC1-5 -alkyloxycarbonyl, arylC1-5 alkyl, substituted arylC1-5 alkyl where the aryl substituents are independently selected from one or more members of the group consisting of C1-5 alkyl, C1-5 alkoxy, halogen, amino, C1-5 alkylamino, and diC1-5 alkylamino, phthalimidoC1-5 -alkyl, aminoC1-5 alkyl, diaminoC1-5 alkyl, succinimidoC1-5 alkyl, C1-5 alkylcarbonyl, arylcarbonyl, C1-5 alkylcarbonylC1-5 alkyl, aryloxycarbonylC1-5 alkyl;
R4 is (A)--(CH2)q --X where;
A is vinylene, ethynylene or ##STR38## where R5 is selected from the group consisting of hydrogen, C1-5 alkyl, phenyl and phenylC1-5 alkyl;
q is 0-9;
X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl where one or more substituents are selected from the group consisting of fluorine, bromine, chlorine and iodine), ethynyl, substituted ethynyl (where the substituents are selected from one or more of the group consisting of fluorine, bromine chlorine and iodine, C1-5 alkyl, substituted C1-5 alkyl where the alkyl substituents are selected from the group consisting of one or more C1-5 alkoxy trihaloalkyl, phthalimido and amino, C3-7 cycloalkyl, C1-5 alkoxy, substituted C1-5 alkoxy where the alkyl substituents are selected from the group consisting of phthalimido and amino, phthalimidooxy, phenoxy, substituted phenoxy (where the phenyl substituents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy), phenyl, substituted phenyl where the phenyl substituents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, arylC1-5 alkyl, substituted arylC1-5 alkyl where the aryl substituents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, arylhydroxyC1-5 alkyl amino, C1-5 alkylamino, diC1-5 alkylamino, nitrile, oxime, benxyloxyimino, C1-5 alkyloxyimino, phthalimido, succinimido, C1-5 alkylcarbonyloxy, phenylcarbonyloxy, substituted phenylcarbonyloxy where the phenyl substitutents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, phenylC1-5 alkylcarbonyloxy, where the phenyl substitutents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, aminocarbonyloxy, C1-5 alkylaminocarbonyloxy, diC1-5 alkylaminocarbonyloxy, C1-5 alkoxycarbonyloxy, substituted C1-5 alkoxycarbonyloxy where the alkyl substituents are selected from the group consisting of methyl, ethyl, isopropyl and hexyl, phenoxycarbonyloxy, substituted phenoxycarbonyloxy where the phenyl substituents are selected from the group consisting of C1-5 alkyl, C1-5 alkoxy, and halogen, C1-5 alkylthio, substituted C1-5 alkylthio where the alkyl substituents are selected from the group consisting of hydroxy and phthalimido, C1-5 alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl where the phenyl substituents are selected from the group consisting of bromine, fluorine, chloride, C1-5 alkoxy and trifluoromethyl;
with the proviso;
if A is ##STR39## q is 0 and X is H, R3 may not be SEM; and
pharmaceutically acceptable salts thereof.
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Abstract
This invention relates to a series of substituted imidazoles of Formula I ##STR1## pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention inhibit the production of a number of inflammatory cytokines, and are useful in the treatment of diseases associated with overproduction of inflammatory cytokines.
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Citations
17 Claims
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1. A compound of Formula I ##STR37## wherein:
- R1 is phenyl, substituted phenyl where the substituents are selected from the group consisting of C1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile, or pyridinyl;
R2 is phenyl, substituted phenyl where the substituents are selected from the group consisting of C1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile or pyridinyl where the pyridinyl is optionally C1-4 alkyl substituted; R3 is hydrogen, SEM, C1-5 alkoxycarbonyl, aryloxycarbonyl, arylC1-5 -alkyloxycarbonyl, arylC1-5 alkyl, substituted arylC1-5 alkyl where the aryl substituents are independently selected from one or more members of the group consisting of C1-5 alkyl, C1-5 alkoxy, halogen, amino, C1-5 alkylamino, and diC1-5 alkylamino, phthalimidoC1-5 -alkyl, aminoC1-5 alkyl, diaminoC1-5 alkyl, succinimidoC1-5 alkyl, C1-5 alkylcarbonyl, arylcarbonyl, C1-5 alkylcarbonylC1-5 alkyl, aryloxycarbonylC1-5 alkyl; R4 is (A)--(CH2)q --X where; A is vinylene, ethynylene or ##STR38## where R5 is selected from the group consisting of hydrogen, C1-5 alkyl, phenyl and phenylC1-5 alkyl; q is 0-9; X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl where one or more substituents are selected from the group consisting of fluorine, bromine, chlorine and iodine), ethynyl, substituted ethynyl (where the substituents are selected from one or more of the group consisting of fluorine, bromine chlorine and iodine, C1-5 alkyl, substituted C1-5 alkyl where the alkyl substituents are selected from the group consisting of one or more C1-5 alkoxy trihaloalkyl, phthalimido and amino, C3-7 cycloalkyl, C1-5 alkoxy, substituted C1-5 alkoxy where the alkyl substituents are selected from the group consisting of phthalimido and amino, phthalimidooxy, phenoxy, substituted phenoxy (where the phenyl substituents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy), phenyl, substituted phenyl where the phenyl substituents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, arylC1-5 alkyl, substituted arylC1-5 alkyl where the aryl substituents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, arylhydroxyC1-5 alkyl amino, C1-5 alkylamino, diC1-5 alkylamino, nitrile, oxime, benxyloxyimino, C1-5 alkyloxyimino, phthalimido, succinimido, C1-5 alkylcarbonyloxy, phenylcarbonyloxy, substituted phenylcarbonyloxy where the phenyl substitutents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, phenylC1-5 alkylcarbonyloxy, where the phenyl substitutents are selected from the group consisting of C1-5 alkyl, halogen and C1-5 alkoxy, aminocarbonyloxy, C1-5 alkylaminocarbonyloxy, diC1-5 alkylaminocarbonyloxy, C1-5 alkoxycarbonyloxy, substituted C1-5 alkoxycarbonyloxy where the alkyl substituents are selected from the group consisting of methyl, ethyl, isopropyl and hexyl, phenoxycarbonyloxy, substituted phenoxycarbonyloxy where the phenyl substituents are selected from the group consisting of C1-5 alkyl, C1-5 alkoxy, and halogen, C1-5 alkylthio, substituted C1-5 alkylthio where the alkyl substituents are selected from the group consisting of hydroxy and phthalimido, C1-5 alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl where the phenyl substituents are selected from the group consisting of bromine, fluorine, chloride, C1-5 alkoxy and trifluoromethyl;
with the proviso;if A is ##STR39## q is 0 and X is H, R3 may not be SEM; and
pharmaceutically acceptable salts thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 12, 13, 14, 15)
- R1 is phenyl, substituted phenyl where the substituents are selected from the group consisting of C1-5 alkyl, halogen, nitro, trifluoromethyl, and nitrile, or pyridinyl;
- 8. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(4-hydroxybutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(3-hydroxypropyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4(4-fluorophenyl)-2-(5-hydroxypentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(6-hydroxyhexyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.
- 9. A compound 4-(4-fluorophenyl)-2-(4-hydroxybutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole and pharmaceutically acceptable salts thereof.
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10. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(5-cyanopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-dimethylaminobutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-(phenylcarbonyloxy)butyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(4-methylcarbonyloxy)butyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(3-cyclopentylpropyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(5-(butylsulfonyl)pentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.
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11. A compound and pharmaceutically acceptable salts thereof selected from the group consisting of 4-(4-fluorophenyl)-2-(octyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-butylthiopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-phenylpentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl-2-(5-chloropentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl)-2-(5-hydroxypentyn-1-yl)-1-(3-phthalimidolpropyl)-5-(4-pyridinyl)imidazole, 4-(4-fluorophenyl-2-(pentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole, and 4-(4-fluorophenyl)-2-(5-N-succinimidopentyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridinyl)imidazole.
Specification